Prasterone has the systematic name (3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,10,11,12,13,14,15,16-dodecahydro-1H-cyclopenta[a]phenan- thren-17(2H)-one. This compound has the structure shown:
    This compound has the epiandrosterone polycyclic ring system core, and this ring system is dehydrogenated at the 5-position; thus, this compound is often called “5-dehydroepiandrosterone.” It is one of perhaps twenty different species of mono-dehydrated epiandrostenedione, thus one of twenty possible “dehydroepiandrostenedione” compounds.
Prasterone is dimorphous. Both forms, however, are solid crystals at physiological temperatures (melting point 140-41° for the needle form, 152-53° for the leaflet form). Prasterone is poorly soluble in water (63.5 mg/L water). Prasterone is relatively lipophilic, having a log P (octanol-water)=3.23. Prasterone is thus known in the art as poorly bioavailable.
One solution to this problem has been to simply administer large doses. For example, Fernand LABRIE, U.S. Pat. No. 5,728,688, teaches human clinical testing of daily doses of 1.6 grams per day, see 4:66 et seq. LABRIE also teaches laboratory rat doses of 450 mg/kg, see 3:55 et seq. Given that the average American adult male weight is 86.6 kilograms, and assuming (an incorrect assumption) that there is a 1:1 correspondence between human and rat dosing, this implies a human dose of about 39 grams per day. Such large daily doses, however, may run the risk of precipitating undesired adverse side effects.
The literature is nonetheless quite sparse in teaching approaches to improve prasterone bioavailability. One approach has been to use non-oral delivery routes. For example, Fernand LABRIE, U.S. Pat. No. 5,780,460, teaches “percutaneous or transdermal administration” using a variety of “Gels, solutions, lotions, creams, ointments and transdermal patches.” See e.g., Abstract; see also, e.g., Peter R. CASSON et al., Delivery of Dehydroepiandrosterone To Premenopausal Women: Effects of Micronization and Non-Oral Administration, 174 Amer. Journ. Obst. Gyn. 649 (1996).
Another approach, pioneered by researchers in Italy, employs alpha cyclodextrin to make a clathrate. For example, Paolo CORVI MORA et al., Enhancement of Dehydroepiandrosterone Solubility and Bioavailability by Ternary Complexation with α-Cyclodextrin and Glycine, 92 Journ. Pharma Sci. 2177 (2003), teaches improving the bioavailability of a type of dehydroepiandrosterone (the authors unfortunately fail to specify which of the twenty dehydroepiandrosterones they investigated) by “high-energy cogrinding with α-cyclodextrin” combined with glycine, biomaltodextrin, polyvinyl pyrrolidone and/or polyethylene glycol 400. This approach provided intriguing results. It has two critical failings, however, preventing its commercial use.
First, the method requires grinding in a laboratory-scale device: a high-energy vibrational micromill, see p. 2178. This type of apparatus is not, to my knowledge, used by any manufacturer in the world to manufacture pharmaceutical clathrates on a commercial scale. Thus, translating CORVI MORA (2003) to a commercial scale would require a significant amount of development and experimentation, apparently entailing the design and purchase of custom micromilling machinery. Further, there is no assurance that such an industrial-scale process would be ultimately successful in making a composition with improved bioavailability.
Second, CORVI MORA (2003) produces a material with a physical structure not amenable to structural analysis by known analytical methods. The resulting material, for example, appears to have no definite X-ray diffraction fingerprint. Thus, it is impossible to say whether the resulting material is in fact a clathrate, or is simply an amorphous mixture of the respective components. This inability to clearly characterize the resulting composition because given the materials used, the resulting material is likely not in fact a clathrate.
A clathrate is a complex of a “donut-shaped” cyclodextrin with a lipophilic hole region, which lipophilic hole region houses a lipophilic payload molecule. Dehydroepiandrosterones are lipophilic. Even the smallest of them, however, are simply too large to physically fit in the hydrophobic space present in α-cyclodextrin. The inability to quantitatively assay the resulting material to determine whether or not it is in fact a clathrate frustrates a potential manufacturer's ability to comply with applicable quality-control regulations. Thus, while CORVI MORA (2003) teaches a way (apparently the only way) to improve the bioavailability of an orally-administered dehydroepiandrosterone, it fails to provide the art with an industrial-scale solution.
To address these shortcomings, Paolo CORVI MORA, Clathrates of Dehydroepiandrosterone and Corresponding Pharmaceutical Compositions, PCT Publication WO 00/37109 (2000), teaches (at Example 11) to replace high-energy vibrational micromilling with a more conventional approach to making clathrate complexes: dissolving the dehydroepiandrosterone and alpha-cyclodextrin in a solvent to make a solution, and then removal of the solvent (by spray-drying or lyophilization). CORVI MORA (2000), however, fails to say whether this approach makes a clathrate, nor whether this approach increases or decreases dehydroepiandrosterone bioavailability.
The skilled artisan would infer that CORVI MORA (2000) does not increase dehydroepiandrosterone bioavailability, for two reasons. First, as mentioned above, even the smallest of the various dehydroepiandrosterones is simply too large to physically fit in the hydrophobic space present in αlpha-cyclodextrin. Thus, the skilled artisan would expect the approach taught by CORVI MORA (2000)—dissolution and drying—to result in a simple mixture of dehydroepiandrosterone and alpha-cyclodextrin, not a clathrate complex of dehydroepiandrosterone housed within the hydrophobic region of alpha-cyclodextrin.
Second, CORVI MORA (2000) was followed three years later by CORVI MORA (2003). In the latter (2003) publication, CORVI MORA et al. (at page 2178, col. 1) note that dehydroepiandrosterone has “low and variable bioavailability.” The skilled artisan would thus read CORVI MORA (2003) to teach that CORVI MORA (2000) had not solved the problem of “low and variable bioavailability.”
There thus remains a need for an industrial-scale or commercial-scale way to formulate prasterone (5-dehydroepiandrosterone) to increase its bioavailability and decrease the variability of its bioavailability.